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Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients

Management considerations, screening, and prevention of coccidioidomycosis in immunocompromised individuals and pregnant patients
Literature review current through: Jan 2024.
This topic last updated: Jun 15, 2023.

INTRODUCTION — Patients with impaired cellular immunity are at increased risk for severe or disseminated infection. In these patient populations (eg, patients with HIV and a CD4 count <250 cells/microL, those undergoing transplant, patients initiating tumor necrosis factor inhibitor [TNFi] treatment), certain management aspects should be considered when treating these patients for coccidioidomycosis. In addition, screening for asymptomatic infection is warranted so that antifungal therapy can be administered to reduce the risk of developing symptomatic disease.

This topic will review the principles and strategies of treating coccidioidomycosis and reducing the risk of coccidioidomycosis in patients during pregnancy and/or with immunocompromising conditions. Specifically, we discuss patients with HIV, transplant recipients, and patients receiving immunomodulating therapies.

The antifungal selection in the treatment of coccidioidomycosis in immunocompromised patients is similar to that for immunocompetent patients and is discussed elsewhere. (See "Primary pulmonary coccidioidal infection", section on 'Immunocompromised patients' and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis", section on 'Management'.)

The main discussions on clinical manifestations, diagnosis, and management of pulmonary and extrapulmonary coccidioidomycosis are found elsewhere. (See "Primary pulmonary coccidioidal infection" and "Coccidioidomycosis: Laboratory diagnosis and screening" and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis" and "Coccidioidal meningitis".)

MANAGEMENT CONSIDERATIONS FOR SPECIAL POPULATIONS — Patients with impaired cellular immunity and those who are pregnant warrant extra consideration in management of coccidioidomycosis.

Immunocompromised patients — Cellular immunity is critical to the control of coccidioidomycosis [1]. Animal studies have been supported by clinical observations demonstrating more severe and/or disseminated coccidioidal disease among patients with advanced HIV infection [2], those with solid organ transplants [3], and those receiving anticytokine therapy [4]. Within the UpToDate topics on coccidioidomycosis, use of the term "immunosuppression" or "immunocompromise" refers to depressed cellular immunity and not to depressed humoral immunity.

Immunocompromised patients include:

Patients with HIV and CD4 cell counts <250 cells/microL

Transplant recipients who are on immunosuppression

Patients receiving TNF-alpha inhibitors, high-dose glucocorticoids, and certain other immunomodulators

Patients with solid tumor malignancies who are receiving lymphodepleting chemotherapy [5]

Patients with active hematologic malignancies, as well as those in remission because severe illness has been reported in such patients even after completion of chemotherapy and radiation therapy [6]

Chimeric antigen receptor (CAR)-T cell therapy recipients [7]

Patients with specific gene mutations (interferon gamma receptor [IFN-gammaR1], IL-12 receptor [IL-12Rbeta1] [8], STAT1 [9], and STAT3 [10])

Key differences in management of immunocompromised patients — Patients with impaired cellular immunity are at increased risk for severe disease, dissemination, and reactivation of infection. The general principles of management of coccidioidomycosis in the immunocompromised host (table 1) are the same as those for the normal host, but there are a few major differences:

All immunocompromised patients with clinically active coccidioidomycosis at any anatomic site should receive antifungal therapy because of their high risk for both severe disease and extrathoracic dissemination.

Antifungal therapy is generally prolonged and often lifelong in those who remain immunocompromised. (See 'Duration of therapy' below and 'Secondary prevention' below.)

Minimizing immunosuppression and improving cellular immunity in an immunocompromised patient is a key part of coccidioidomycosis therapy. In patients with HIV, this means initiation of ART as soon as safely possible and monitoring the patient closely for adherence and complications. In patients on immunosuppressive drugs (eg, transplant recipients), this means reduction in dose or complete discontinuation of immunosuppressants, when possible. Patients with specific gene mutations generally require prolonged antifungal therapy and, if possible, immune modulation therapy to overcome the genetic defect.

All such cases should be managed in conjunction with an infectious diseases expert who is experienced in the treatment of coccidioidomycosis.

Patients with HIV — The United States Department of Health and Human Services and the Infectious Diseases Society of America both have sections on coccidioidomycosis management in patients with HIV [11,12]. Our recommendations are generally in keeping with these guidelines. Most cases identified within coccidioidal-endemic areas appear to be due to recent acquisition, although it can occasionally be due to reactivation of previously acquired infection [13,14].

Role of CD4 count and antiretroviral therapy — A low peripheral blood CD4 lymphocyte count (CD4 cell count <250 cells/microL), and hence a reduced cellular immune function, is the most important factor in determining whether a person with HIV will develop symptomatic coccidioidomycosis following exposure [15].

Management of coccidioidomycosis in persons with HIV depends upon immune status and the severity of disease. The basic principles of managing coccidioidomycosis in persons with HIV are summarized below:

For patients with CD4 cell counts ≥250 cells/microL, management should be the same as in healthy patients without underlying immunodeficiency. (See "Primary pulmonary coccidioidal infection", section on 'Immunocompetent nonpregnant patients' and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis", section on 'Approach to treatment'.)

For patients with CD4 cell counts <250 cells/microL, antifungal therapy should be initiated and continued for the duration of treatment and until the CD4 cell count is ≥250 cells/microL and viral load is suppressed for at least three months. (See 'Secondary prevention' below.)

In a prospective cohort study performed in the era before the introduction of potent combination antiretroviral therapy (ART), approximately 25 percent of persons with HIV living in an endemic region developed symptomatic coccidioidomycosis [2], and the main risk factor was a CD4 count <250 cells/microL or a clinical diagnosis of AIDS. Lack of in vitro response to coccidioidal antigen and presumed lack of protective immunity have been found to be associated with a CD4 cell count of <250 cells/microL [15].

Initiating antiretroviral therapy — In general, we initiate antiretroviral therapy (ART) in newly diagnosed patients with HIV and CD4 cell count ≥250 cells/microL with coccidioidomycosis as soon as possible. In those with active coccidioidomycosis who are diagnosed coincidently with HIV and in whom the CD4 cell count is <250 cells/microL, it may be prudent to start antifungal therapy four to eight weeks prior to initiating ART, particularly in those with coccidioidal meningitis. All such patients should be closely monitored.

The use of potent combination ART, which results in virologic suppression, increased CD4 cell counts, and immune restoration, has decreased the incidence of symptomatic coccidioidomycosis in persons with HIV and is the most important factor in preventing and treating symptomatic coccidioidomycosis in persons with HIV [16-18]. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

Immune reconstitution inflammatory syndrome — Instances of immune reconstitution inflammatory syndrome (IRIS) have been reported in patients with coccidioidomycosis [19-23]. Most patients have had active coccidioidomycosis at the time of initiation of ART and all had CD4 cell counts <150 cells/microL. In several cases, patients developed worsening coccidioidomycosis despite being on both antifungal therapy and ART [19,22], suggesting that such patients should be closely monitored.

There are scant data on the most appropriate way to manage a person with HIV and IRIS due to coccidioidomycosis. We continue both antifungal therapy and ART and consider adding corticosteroids, although there is a lack of data on the latter. A more detailed discussion of IRIS is presented elsewhere. (See "Immune reconstitution inflammatory syndrome".)

Patients taking immunomodulatory agents — Patients receiving antagonist therapy against tumor necrosis factor-alpha inhibitors (TNFi) are at increased risk for symptomatic and disseminated coccidioidomycosis [4]. For other anti-cytokine and related therapies, the risk is far less clear and is discussed elsewhere. (See 'Indications for screening' below.)

In cases of symptomatic coccidioidomycosis, we withhold TNFi for at least six weeks and simultaneously initiate antifungal treatment (table 1) because of the risk of severe disease and possible dissemination [4,24]. If after six weeks, the patient has clinically improved, it may be reasonable to restart TNFi therapy.

Duration of therapy — Immunosuppressed patients may improve more slowly and require longer treatment durations than nonimmunosuppressed individuals. The duration of treatment ultimately depends on the clinical, serologic, and radiographic responses as well as the severity and duration of the cellular immunosuppression. We look for resolution of symptoms, significant improvement in radiographic findings, and a complement-fixation serology titer of ≤1:4. In general, we treat patients with pulmonary coccidioidomycosis for at least 6 to 12 months and extrapulmonary disseminated disease for at least 12 months, but longer courses may be required. In some cases in which immunosuppression is persistent, lifelong therapy may be appropriate.

After completion of therapy, patients should continue to receive secondary prophylaxis to prevent recrudescence of infection while they remain on immunosuppressive therapy. (See 'Secondary prevention' below.)

Secondary prevention — Due to the risk of reactivation, secondary prevention is beneficial for patients who have completed treatment for coccidioidomycosis but remain immunocompromised, such as patients with HIV and CD4 cell count <250 cells/microL or patients who continue taking immunosuppressive agents. We typically decrease the fluconazole dose to 200 mg orally daily for secondary prevention. If patients are taking other oral azoles, a decision should be made with the patient regarding whether to switch to fluconazole or continue the other azole.

We continue secondary prevention until the patient is no longer immunocompromised. In some individuals, this may mean lifelong antifungal therapy.

In patients with impaired cellular immunity, there are no data to guide the duration of monitoring after the initial few years. We perform a coccidioidal serology and appropriate imaging annually for as long as the immunosuppression continues.

Pregnant patients — There are several important issues surrounding coccidioidomycosis and pregnancy [25].

Serologic screening – We do not routinely serologically screen pregnant individuals who reside in a coccidioidal-endemic region, regardless of whether they previously had coccidioidomycosis [26,27]. Pregnant females who have acquired infection prior to pregnancy generally control their infection and do not require therapy.

Indications for treatment – The decision to treat pregnant females with evidence of active coccidioidomycosis depends on the stage of pregnancy and the manifestations of coccidioidal illness. Management of pregnant patients with coccidioidomycosis should be done in consultation with an expert in coccidioidomycosis.

Severe and/or extrathoracic disease – Treatment is indicated for all pregnant females with severe and/or extrathoracic infection.

Mild or moderate pulmonary disease – For pregnant individuals with mild to moderate coccidioidomycosis, clinicians should engage in shared decision-making with their patients after discussing risks and benefits of initiating therapy.

-Females in their first trimester of pregnancy who present with mild to moderate primary pulmonary disease or a positive coccidioidal serology without clinical illness typically do not require antifungal therapy. In such cases, careful clinical monitoring with clinical evaluation and serology every 6 to 12 weeks is appropriate. Increasing titers are concerning for more active disease and warrant further discussion with the patient regarding initiating therapy.

-Individuals who acquire coccidioidomycosis during second or third trimester or within six weeks postpartum are at increased risk for developing severe or disseminated disease during that period and should be followed very closely [25,28]. Decision to initiate treatment in these patients is made on a case-by-case basis, taking into account the patient's preferences, the severity of the symptoms, the risk of azoles to the fetus, and the trajectory of the coccidioidal antibody titer, and should be done in consultation with an expert in coccidioidomycosis.

For females who are receiving azole antifungal treatment for coccidioidomycosis when they become pregnant, we discontinue the azole and initiate amphotericin B for the duration of the first trimester. We also obtain new baseline serologic testing and perform a clinical evaluation every 6 to 12 weeks to monitor clinical status and progression. Nonpregnant females with active coccidioidomycosis who are on triazole antifungal therapy should be advised to consider foregoing pregnancy while on therapy and to consider, if possible, stopping therapy prior to becoming pregnant.

Pregnant females with coccidioidomycosis should be managed in conjunction with an infectious diseases specialist.

The fetus and newborn are rarely affected by maternal coccidioidomycosis [29]. IgG coccidioidal antibody may be detected in the serum of newborns of mothers with recent infection. This is usually a result of passive transfer of maternal antibody and in itself does not indicate infection [30]. (See "Unusual fungal infections in the neonate", section on 'Coccidioidomycosis'.)

Antifungal selection – Triazole antifungals should be avoided during the first trimester of pregnancy given the potential risk of teratogenicity [31-33] as well as spontaneous abortion and stillbirth [34,35]. This may require the use of intravenous amphotericin B in those with active nonmeningeal coccidioidomycosis and intrathecal amphotericin B in those with active meningeal coccidioidomycosis during this period.

After the first trimester, it may be reasonable to initiate a triazole antifungal, but this should be done on a case-by-case basis after careful consultation with the patient, obstetrician, and infectious diseases expert. (See "Pharmacology of azoles", section on 'Pregnancy'.)

SCREENING AND PREVENTION IN IMMUNOCOMPROMISED INDIVIDUALS

Reducing environmental exposure — It is impossible to completely avoid exposure to coccidioidomycosis in the endemic area because the fungus is frequently present in ambient air [36]. However, we do counsel at-risk patients to stay inside during dust storms and avoid activities that result in exposure to local dust or desert soil. Patients visiting these areas should also be educated about the use of these precautions. With specific exceptions noted below (solid organ transplantation, hematopoietic cell transplantation), we do not routinely recommend the use of long-term antifungal prophylaxis for the primary prevention of coccidioidomycosis, as this has not been found to be effective [17].

Approach to serologic screening — Serologic tests are used for screening for coccidioidomycosis. Several different serologic tests are available. Enzyme-linked immunoassays (EIAs) for immunoglobulin M (IgM) and IgG detection are widely available and have high sensitivity but are not as specific as immunodiffusion (ID; detecting IgM and IgG) and complement-fixation (CF; detecting IgG) serologic tests, which are only found in certain reference laboratories. EIA IgM, in particular, is very prone to false-positive results, especially when screening for infection in the absence of symptoms. Hence, every positive EIA IgM serology must be confirmed by a positive EIA IgG or a positive immunodiffusion and CF test.

There are two approaches to using serologic tests for screening:

One of the authors orders the EIA first and only proceeds with ordering the ID and CF tests if the EIA is positive. This approach is a cost-effective and appropriate option for screening populations at low risk for coccidioidal disease.

However, the other author orders both the EIA and the ID and CF tests at the same time to obtain the most information regarding current or past evidence of coccidioidomycosis. This approach allows for detection of the small percentage of patients who may have a negative EIA but positive ID and/or CF titer.

Serologic testing is combined with a clinical and radiographic evaluation for symptoms and/or signs of active or remote coccidioidal disease. Presence of symptoms, signs, or radiographic abnormalities suggestive of a pulmonary infection in the setting of negative coccidioidal serology warrants further evaluation (including for coccidioidomycosis), with fluid or tissue sample collection that can be sent for culture and histopathology.

Patients with HIV — We screen all patients with HIV and a CD4 cell count ≤250 cells/microL who live in endemic areas with coccidioidal serology and chest imaging every six months, usually at the same time as routine HIV RNA and CD4 cell count evaluation. If coccidioidal serology is positive, we initiate pre-emptive therapy with an oral triazole (eg, fluconazole 400 mg orally daily) and continue therapy until the CD4 cell count is >250 cells/microL and viral load is suppressed for at least three months [37]. In addition, we discuss ways to reduce environmental exposure and emphasize that the use of antiretroviral therapy (ART) is the most effective way to prevent the development of severe coccidioidomycosis. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

Transplant recipients

Screening prior to transplantation — It is important to identify transplant candidates who may be at risk of reactivating asymptomatic coccidioidal infection post-transplantation or those who may be harboring an asymptomatic infection [38,39]. Because of this, we screen all solid organ and hematopoietic cell transplant candidates if they live in, have lived in, or traveled in an endemic area. We do not typically screen patients who have only temporarily visited endemic areas (eg, one week or less), since the pretest probability of infection is low, and a false-positive test could mean life-long prophylaxis. However, serologic testing should be performed in these low-risk patients if they have symptoms that could be consistent with coccidioidomycosis. (See "Primary pulmonary coccidioidal infection", section on 'When to suspect infection' and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis", section on 'Initial evaluation'.)

Screening involves an assessment for both active and past infection based upon history, serology, and chest radiograph.

For patients with positive coccidioidal serology and chest radiograph findings and/or symptoms consistent with active coccidioidomycosis, we initiate antifungal therapy and defer transplant until it is clinically evident that the coccidioidal infection is controlled. Transplant can then proceed with the patient continuing treatment post-transplantation. Transplant candidates with positive coccidioidal serology should be managed by an infectious diseases consultant. (See 'Immunocompromised patients' above and "Primary pulmonary coccidioidal infection", section on 'Immunocompromised patients' and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis", section on 'Approach to treatment'.)

For all other patients without clinical evidence of active coccidioidal disease, such as an asymptomatic patient with isolated positive coccidioidal serology or negative coccidioidal serology, no treatment is necessary until post-transplantation. (See 'Preventive therapy in solid organ transplant recipients' below and 'Preventive therapy in hematopoietic cell transplant recipients' below.)

Preventive therapy in solid organ transplant recipients — We administer preventive therapy post-transplantation to patients at risk for new infection or reactivation, or who received an organ from a donor with coccidioidomycosis [40]. Active coccidioidomycosis can result in serious morbidity and mortality in patients undergoing solid organ transplantation (SOT) [3,39,41-47]. Active disease can result from reactivation of old disease or from primary infection after transplant. The latter is usually related to environmental exposure, but rarely, infection can be transmitted directly from the donor organ [45,47-50].

Recipients with negative serology living outside of endemic areas – Prophylactic antifungal therapy against coccidioidomycosis is not necessary in asymptomatic SOT recipients with negative serology and normal chest imaging who do not reside in coccidioidal-endemic areas, even if they have a remote history of coccidioidomycosis.

Recipients at risk for new infection – For all SOT recipients who reside in areas that are endemic for Coccidioides species and who are without evidence of remote or active infection (negative history, serology, and chest radiograph), we initiate fluconazole (400 mg daily) at the time of transplantation and continue it for 6 to 12 months.

This approach to prophylaxis has been shown to markedly reduce the number of new coccidioidal infections in the first post-transplant year in liver transplants [51]. A study in heart transplant patients demonstrated similar findings [52]. In a retrospective study, use of triazole antifungals was associated with a lower risk of coccidioidomycosis among lung transplant recipients living in the coccidioidal-endemic region [53], and a study of universal long-term triazole antifungals, mostly itraconazole, in another group of lung transplant recipients from the endemic region was associated with only one case of active coccidioidomycosis among 493 cases [40,54]. Recently, it has been noted that universal antifungal prophylaxis to prevent coccidioidomycosis in SOT may result in an increased risk of candidiasis due to species other than C. albicans [55].

Recipients at risk for reactivation from latent or subclinical disease – Patients at risk for reactivation are asymptomatic patients who either have a positive coccidioidal serology and a negative chest radiograph at the time of transplantation or have a recent (eg, within the last two years) diagnosis of coccidioidomycosis with evidence of a pulmonary nidus (eg, nodule) on imaging but with negative coccidioidal serology. Unlike many other infections, a positive coccidioidal serology is not an indication of protection and indicates some degree of ongoing disease activity, even in the absence of symptoms. For these patients, we administer one year of fluconazole at a dose of 400 mg daily and then reduce the dose to 200 mg daily. Although the optimal duration for ongoing prophylaxis is unknown, we continue treatment while the patient remains on immunosuppressive therapy. (See 'Secondary prevention' above.)

Our approach is based upon our experience with patients undergoing liver, pancreas, kidney, and/or heart transplant [45,46,51]. In a retrospective study of patients undergoing SOT at the authors' center, 44 were identified as having a history of and/or serologic evidence of prior coccidioidal infection without evidence of active disease [46]. Of these, 37 received fluconazole following transplantation and none had evidence of reactivated infection; the remaining 7 either did not receive postoperative fluconazole or were not adherent to treatment, and 2 had reactivation of coccidioidomycosis.

Recipients who receive an organ from a donor with evidence of coccidioidomycosis – There have been several reports of coccidioidomycosis transmission from a donor after SOT [48,49,56]. We treat recipients who receive an organ from a donor with evidence of coccidioidomycosis at the time of transplant with fluconazole 400 mg daily for at least a year, and possibly for life. Since there are no data to guide this decision, the ultimate duration must be made on a case-by-case basis.

Preventive therapy in hematopoietic cell transplant recipients — The indications for and duration of preventive therapy against coccidioidomycosis in hematopoietic cell transplant (HCT) recipients are outlined below.

Patients living in endemic areas – For patients living in endemic areas, we administer fluconazole 400 mg daily for two years regardless of serology based on prior studies indicating a high mortality in those who develop coccidioidomycosis [39,57-59]. Other triazole antifungals can be considered based on availability, cost, and toxicity profile.

For patients with negative serology, fluconazole can be stopped after two years.

For patients with positive serology or imaging findings consistent with coccidioidomycosis in patients with history of coccidioidomycosis, we continue fluconazole while the patient remains on immunosuppressive therapy. (See 'Secondary prevention' above.)

Patients living outside of endemic areas – For patients who are not living in endemic areas at the time of their transplant but met criteria for coccidioidal screening, prophylaxis depends on serology.

If serology is negative and there is no evidence of coccidioidal infection on imaging, no prophylaxis is needed.

If serology is positive or imaging is concerning for residual coccidioidal infection in a patient with a history of coccidioidomycosis, we administer fluconazole for at least two years and continue while patient remains on immunosuppressive therapy. (See 'Secondary prevention' above.)

Patients receiving immunomodulatory agents

Indications for screening — Immunomodulatory agents vary in the degree and type of immunosuppression they cause. Patients receiving tumor necrosis factor-alpha inhibitors (TNFi) [4] or the janus kinase (JAK) inhibitor ruxolitinib [60] are at increased risk for symptomatic and disseminated coccidioidomycosis [4,60].

The risk is far less clear and appears to be low in patients receiving other anti-cytokine and related therapies, such as anti-interleukin (IL)-12 therapy (eg, ustekinumab), anti-IL-17 therapy (eg, secukinumab and ixekizumab), and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy (eg, abatacept). There is also one report of an association of ibrutinib with reactivation of coccidioidal infection [61]. However, based on their mechanism of action, these agents could decrease the immune control of coccidioidomycosis. Caution is advised when using any of these agents, and close monitoring for development or recrudescence of coccidioidomycosis should be implemented.

Other immunomodulatory agents, such as vedolizumab or JAK inhibitors besides ruxolitinib, have had no reported cases of severe or worsening coccidioidomycosis and do not appear to increase the risk of coccidioidomycosis.

There is no established guidance for other immunomodulating drugs such as methotrexate, azathioprine, and leflunomide. Although such patients appear to be at increased risk for developing severe coccidioidomycosis [62], there are insufficient data to suggest screening for infection prior to initiating therapy. The approach to each patient should be individualized.

Screening prior to initiating immunomodulators — Although we will focus on the approach to management of patients initiating TNFi in this section, other patients at high risk (eg, patients initiating ruxolitinib) should follow the same principles. Nevertheless, the approach to each patient should be highly individualized since the data guiding screening and preventive therapy in this patient population are scarce [4,24,62].

Screening prior to starting immunomodulating therapy – We screen all patients living or who have lived in coccidioidal-endemic areas for coccidioidomycosis with serology prior to initiating TNFi therapy [4,24,62].

If serology is negative, no preventive therapy is necessary.

If the EIA and/or ID serology is positive but CF titer is negative, we evaluate for active infection with a history and physical examination. If there is no evidence of active infection, we start TNFi therapy, hold off on antifungal therapy, and monitor for signs and symptoms of coccidioidomycosis periodically (eg, every 12 weeks) with repeat serology, clinical evaluation, and chest radiograph while the patient remains on immunosuppressive therapy.

If the coccidioidal CF titer is ≥1:2, we obtain a chest radiograph and perform a clinical evaluation to assess for symptoms and signs attributable to coccidioidomycosis. If any symptoms or signs consistent with coccidioidomycosis are present, we defer TNFi therapy until treatment for coccidioidomycosis is complete and the patient is asymptomatic (if symptoms were present initially). For patients who are unable to defer TNFi therapy, we start antifungal therapy concurrently with TNFi and monitor clinically with repeat imaging and serology. If there is no evidence of active disease but the titer is positive, we initiate fluconazole and continue the TNFi therapy.

Positive serology while on immunomodulating therapy – If a patient is found to have positive coccidioidal serology or an abnormality on pulmonary imaging and is already receiving a TNFi, we assess the patient for symptoms of coccidioidomycosis and monitor the pulmonary infiltrate. If there is evidence of active (symptomatic), progressive (worsening pulmonary infiltrates) disease or if the coccidioidal CF titer is positive (≥1:2), the patient should be started on coccidioidomycosis treatment. If the patient is asymptomatic, we choose not to stop the TNFi; in patients with symptoms of coccidioidomycosis, we stop the TNFi and restart once the symptoms resolve and serology is stabilized. If none of the above are present, the patient can be monitored every three months without starting antifungal therapy.

Although screening is commonly performed, the data supporting the usefulness of coccidioidal serologic screening prior to and subsequently after initiating TNFi are conflicting. In a retrospective study evaluating approximately 2000 patients, screening and management of asymptomatic infection prior to initiating TNFi were associated with a lower rate of subsequent symptomatic coccidioidomycosis compared with populations that were not screened (1.3 versus 3.4 percent) [63]. However, in another retrospective study of 19 asymptomatic patients receiving disease-modifying antirheumatic drugs (12 on TNFi) with positive coccidioidal serology, there were no cases of active coccidioidomycosis after medial follow up of 43 months in both the group that received antifungal therapy (6 out of 19) and those who did not (13 out of 19) [64].

Data concerning ruxolitinib are even more sparse. In a retrospective review of 135 ruxolitinib recipients who resided within the coccidioidal-endemic area, eight (6 percent) patients with coccidioidomycosis were identified, four of whom had multifocal dissemination [60].

There are no data indicating that other JAK inhibitors (eg, tofacitinib, baricitinib, and upadacitinib) have the same potential to cause widespread dissemination as ruxolitinib.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Opportunistic infections in adults with HIV" and "Society guideline links: Coccidioidomycosis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Valley Fever (coccidioidomycosis) (The Basics)")

SUMMARY AND RECOMMENDATIONS

Management considerations in immunocompromised individuals Cellular immunity is critical to the control of coccidioidomycosis, and patients with impaired cellular immunity are at increased risk for severe and/or disseminated disease. (See 'Key differences in management of immunocompromised patients' above.)

Immunocompromised patients include:

-Patients with HIV and CD4 cell counts <250 cells/microL

-Transplant recipients who are on immunosuppression

-Patients receiving tumor necrosis factor (TNF) alpha inhibitors, high-dose glucocorticoids, and certain other immunomodulators

-Patients with solid tumor malignancies who are receiving lymphodepleting chemotherapy

-Patients with active hematologic malignancies, as well as those in remission since severe illness has been reported, even in such patients after completion of chemotherapy and radiation therapy

-Chimeric antigen receptor (CAR)-T cell therapy recipients

-Patients with specific gene mutations (interferon gamma receptor [IFN-gammaR1], IL-12 receptor [IL-12Rbeta1], STAT1, and STAT3)

All immunocompromised patients with clinically active coccidioidomycosis at any anatomic site should receive antifungal therapy because of their high risk for both severe disease and extrathoracic dissemination. (See "Primary pulmonary coccidioidal infection", section on 'Immunocompromised patients' and "Manifestations and treatment of nonmeningeal extrathoracic coccidioidomycosis", section on 'Approach to treatment'.)

Antifungal therapy is generally prolonged and often lifelong in those who remain immunocompromised. (See 'Duration of therapy' above and 'Secondary prevention' above.)

Minimizing immunosuppression and improving cellular immunity in an immunocompromised patient are a key part of coccidioidomycosis therapy. (See 'Key differences in management of immunocompromised patients' above and 'Role of CD4 count and antiretroviral therapy' above and 'Patients taking immunomodulatory agents' above.)

Management considerations in pregnant individuals

Treatment is indicated for pregnant females with severe or extrathoracic dissemination of infection. (See 'Pregnant patients' above.)

Triazoles should be avoided during the first trimester of pregnancy given the potential risk of teratogenicity as well as spontaneous abortion and stillbirth. (See 'Pregnant patients' above and "Pharmacology of azoles", section on 'Pregnancy'.)

Screening and prevention in immunocompromised individuals

Rationale for screening – Patients with depressed cellular immunity are at increased risk of developing severe and/or disseminated coccidioidomycosis. (See 'Introduction' above.)

Reducing environmental exposure – It is impossible to completely avoid exposure to coccidioidomycosis in the endemic area because the fungus is frequently present in ambient air. However, we counsel at-risk patients to stay inside during dust storms and avoid activities that result in exposure to local dust or desert soil. (See 'Reducing environmental exposure' above.)

Approach to serologic screening

-Various serologic tests are available for screening for coccidioidomycosis. The enzyme immunoassay test is more available and more sensitive; the immunodiffusion (ID) and complement-fixation (CF) tests are more specific but only found in reference laboratories. (See 'Approach to serologic screening' above.)

-Serologic testing is combined with a clinical and radiographic evaluation for symptoms and/or signs of active or remote coccidioidal disease. Presence of symptoms, signs, or radiographic abnormalities suggestive of a pulmonary infection in the setting of negative coccidioidal serology warrants further evaluation (including for coccidioidomycosis), often with fluid or tissue sample collection that can be sent for culture and histopathology. (See 'Approach to serologic screening' above.)

Patients with HIV – For patients with HIV and CD4 cell count <250 cells/microL who live in endemic areas, we screen for coccidioidomycosis every six months to identify those who need pre-emptive therapy to prevent severe and/or disseminated disease. If coccidioidal serology is positive, we initiate pre-emptive therapy with an oral triazole (eg, fluconazole 400 mg orally daily) and continue therapy until CD4 cell count is >250 cells/microL for at least three months. (See 'Patients with HIV' above.)

Transplant candidates – For transplant candidates, we screen for all patients who are living, who have lived, or who have traveled extensively (>1 week at a time) in endemic areas. Patients who are found to have active coccidioidal disease should complete antifungal treatment prior to transplant. For patients without active coccidioidal disease, duration of preventive therapy post-transplantation depends on whether the patient still lives in an endemic area and on serology results. (See 'Transplant recipients' above.)

Patients receiving immunomodulatory agents – We screen for coccidioidomycosis in patients who are initiating or receiving TNF alpha inhibitors or the janus kinase (JAK) inhibitor ruxolitinib. There are insufficient data to suggest screening for coccidioidomycosis prior to initiating other immunomodulatory drugs. We closely monitor patients who live or have lived in an endemic area for recrudescence or development of coccidioidomycosis. (See 'Patients receiving immunomodulatory agents' above.)

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Topic 2418 Version 22.0

References

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